Agios Pharmaceuticals, Inc. (AGIO) Earnings Call Transcript & Summary

Okay, great. Welcome, everyone. This is a multi-company panel entitled Sickle Cell, Beta-Thal, ITP & PKD - Measuring Industry Progress in Benign Hematology. It's my pleasure to introduce the guests on the panel. From Agios Pharmaceuticals, Jackie Fouse, who is the CEO of the company. Hi, Jackie. From Rigel Pharmaceuticals, Raul Rodriguez, the President and CEO; and Jonathan Schwartz, who is the CMO at Rocket Pharmaceuticals. And we have a fourth participant and hopefully will show up soon, Rahul Ballal, the CEO of IMARA. So welcome all of you. Thank you very, very much for your participation.

Maybe to get things started, for those less familiar with your companies and your pipelines, if each of you could spend 2 or 3 minutes just doing a high level, a summary of what you're focused on and what your pipeline looks like. Jackie, you want to kick it off?

Sure. Thanks for having us today, and thanks to my fellow panelists. We'll have a good discussion, I'm sure. So Agios is, as you may or may not know, was founded in 2008 on a research platform in cellular metabolism, and that is still our research focus today. We brought IDH inhibitors to the oncology market, and then many of you may have followed our developments over the last year or so where, along the way, we also elucidated the biology of PKR activation, specifically for the treatment of non-oncology nonmalignant hematology indications that we'll talk about today. And as that developed, we made the decision announced in December of last year that we were going to divest our oncology business and focus solely our science of cellular metabolism on genetically-defined diseases outside of cancer. So we've completed that transition of those oncology assets to a company called Servier, and we're working very hard on that over the first part of this year and are now able to look forward. We closed that deal on March 31, have successfully transitioned those assets. And our scientific platform remains the same. We're just focusing our cellular metabolism efforts in -- outside of oncology, and so we're moving forward with programs in PKD, pyruvate kinase deficiency; in thalassemia, both beta and alpha thal; and sickle cell disease and some other things that we're working on at earlier stages, but we hope to have a commercial approval for mitapivat, our lead asset in pyruvate kinase deficiency, where we have a PDUFA date now of February 17, 2022. So that's imminent. And that's where we are.

Thank you. Raul?

Sure. Good to see you again. Again, thank you for inviting us to speak on the panel. Rigel is a biotech company in the San Francisco area. Our focus is hematology oncology and rare immune diseases. And then most recently, as of last year, COVID therapeutics area as well. I'll tell you about each of those. So our lead product is a product named TAVALISSE. TAVALISSE is a SYK kinase inhibitor. And SYK kinase is important in many immune cell signaling. And we have -- we're pursuing 2 hematologic indications. One is ITP or immune thrombocytopenia. And immune thrombocytopenia purpura is an autoimmune disease where the body destroys its own circulating platelets. Signaling this destruction occurs through by macrophages, signaling to SYK kinase. So TAVALISSE was approved for the treatment of adult ITP in 2018. So we built a commercial organization, launched the product successfully in 2018 and made good progress in making the product available in the treatment of ITP. In addition to that, a companion indication that's almost exact a perfect follow-up indication is warm autoimmune hemolytic anemia. And warm autoimmune hemolytic anemia, as the name implies, is also an autoimmune disease where the body now destroys its own circulating red blood cells. So people who suffer from warm autoimmune hemolytic anemia have very suppressed hemoglobin, fatigue, difficulty functioning. Our product is the most advanced product in the study in warm autoimmune hemolytic anemia. We had some very nice Phase II results, the only Phase II results so far produced in this area. And we are finishing enrollment in our Phase III study for warm autoimmune hemolytic anemia. And we hope later this year to have that enrollment completed so that then we can be the first-to-file and ultimately, the first to get an approval for the treatment of warm autoimmune hemolytic anemia. So these 2 hematologic indications, I think, work well together. Same doctors, heme-oncs, hematologists treat both of these indications. And so right now as we're building awareness of our mechanism or our product with these doctors with ITP, that will be completely translatable to more warm autoimmune hemolytic anemia when we get that approved.

Okay. Great. And Jonathan?

Hi, I'm Jonathan, Rocket's Chief Medical Officer. And Rocket is a company that's focused on genetic diseases and specifically on life-threatening disorders, both of the hematopoietic system and other systems as well. We have 5 clinical stage programs. One of these programs is an AAV-based therapy for Danon disease, which is a very aggressive cardiomyopathy, and we'll not focus on that. And the other 4 programs are Fanconi anemia, leukocyte adhesion deficiency I, pyruvate kinase deficiency and infantile malignant osteopetrosis. The 2 programs that are in registrational phase study are Fanconi anemia, which is a DNA repair and bone marrow failure disorder in which 80% patients experience bone marrow failure during the first decade of life in the absence of an allogeneic transplant. Allogeneic transplant is successful at averting bone marrow failure, but obviously comes with short and longer-term toxicities, including an amplification of the already high risk of subsequent solid tumors that Fanconi anemia patients face. Leukocyte adhesion deficiency I and specifically the severe variant is a neutrophil disorder that renders neutrophils incapable of leaving the bloodstream and finding infection based on a deficiency of a critical receptor of CD18 integrin. In the absence of this integrin, survival in the absence of an allogeneic transplant is very limited, with some studies showing survival to age 2 as low as anywhere from 25% to 40%. And so very high unmet need in that disorder. Red blood cell pyruvate kinase deficiency is something that Jackie was already able to cover. Rocket's gene therapy program is, at present, focused on the more severe end of the spectrum for that disease. And we have been able to present our initial results in the first 2 adult patients, both of whom had extremely low hemoglobins in the 7 or 7.5 range and currently multiple months after therapy have been stable with hemoglobins really in the 12- to 13-gram per deciliter range and evidence of vastly reduced hemolysis. And we will be initiating or have initiated investigation into pediatric population with equally very severe PKD who have ongoing severe anemia or transfusion requirements despite having had a splenectomy. And then the fourth program, which just really began clinical stage development, is the infantile malignant osteopetrosis, which is a dreadful disease where osteoclasts, the cells that resorb bone, fail to function. And as a result, the children during the very first year of life develop very dense, abnormal bones and have tremendous endocrine, neurologic and bone marrow failure complications as a result of their inability to grow and remodel bone. And that's a program that also represents an extremely high unmet need during the very first years of life.

Thanks. Well, you're all pursuing some very interesting programs. I'm curious though as to how you go about picking which rare heme indications you pursue. Is there some strategy there? Is it -- do you have a molecule and then you look for an indication? Help us understand. For example, with PKD, Jackie, how you gravitated towards that indication. And Raul, with ITP, how it is that you ended up focusing on ITP first. And then, of course, Jonathan, you mentioned 5 different diseases. But for example, how did Fanconi anemia and PKD, how did you arrive at those? So Jackie, do you want to start?

Sure. Thanks for that. So when we first started to elucidate the biology around PKR activation and then look at what that potential would hold for patients, we focused on the diseases where we thought that it might bring some benefit. And then initially, we were looking at mutations. And so that's how we ended up with PKD, because we were -- we knew that the drugs that we were -- had discovered and were developing would work on the mutated form of the enzyme. And so that -- we started with that. And then, of course, we looked at the fact that there's unmet medical need. There's no approved treatment options for those patients today and those sorts of things. But we're really focused on the biology first and then how the mechanism can help these patients. Along the way, then we also figured out that our drug activated wild type and that took us then into thalassemia and sickle cell disease. And what's been really interesting about it is that we've learned from each one of those indications along the way, including a lot about the safety profile of our drug. So I think you may not know, when you first have your initial indication for how you think you're going to come at things, all of that you're going to learn that may benefit you as you look at other indications that would come along. Clearly, from a business model standpoint, it's interesting to be able to come to market with that product that there's no treatment alternatives for, at least when we come with mitapivat, and then take it into successively greater numbers of patients with the indication expansion. But I'm not sure at the time that we targeted PKD because of coming at it from the mutation standpoint that we really realized that, that's exactly where we were going to be able to go with the drug. But when you think about the some of the common attributes of these hemolytic anemias, then you -- there are some things that you could flesh out and learn there.

Makes sense. Raul?

Yes. So with our lead product, fostamatinib or TAVALISSE, a SYK inhibitor. We were excited about the potential of the molecule because SYK inhibition and autoimmune diseases is just such a broad area. Large diseases like RA, as well as smaller diseases, rare diseases like ITP or autoimmune hemolytic anemia. And that's what's excited us about the mechanism. And then we proceeded to do clinical trials in rheumatoid arthritis showing benefit. For a small company like ourselves, though, smaller indications like ITP or warm autoimmune hemolytic anemia are really much more attractive in the sense that, generally, medical need is very great there. It's fully addressed markets. For example, in warm AIHA, nothing is approved in that indication. So we would be the first approved in that indication to provide a product to those patients suffering from AIHA. And so the need is usually greater in the smaller indications, and our mechanism is a very good fit for the process that underlies ITP and AIHA. They both are fundamentally autoimmune diseases where the body's immune system destroys platelets or red blood cells, respectively. And those patients suffer from a deficit of those cells. And we, with TAVALISSE, can stop that destructive process and therefore, increase platelets or blood cells to the benefit of those patients. So really, we look at it from a -- here's the mechanism that we're interested in and why, but it has to be a mechanism that addresses diseases that we care about. And we certainly care about heme-onc diseases, specifically autoimmune ones with this drug. And is there a medical need? That's a key consideration. And finally, I think this is maybe a little less discussed. We have to be able to do it, and that is the size of the trials, the size and the expense and the time that [indiscernible] you can execute on them. And one of the things that I like about hematology indications is that the blood is readily available. You take a blood count, you take a blood sample and you count. For example, in platelets, the measure is increasing platelet counts. So you have to just count the platelets. Highly objective, anywhere -- anywhere -- I think we count almost anywhere. It's not a challenging thing to count or count platelets. If you're over 50,000, that's a good thing. If you're under 50,000 or under 30,000, and you can't get there, well, that's not a good thing. It's easy to count. It's highly objective, and that's one of the benefits of being in hematology as a benefit. And the ability to do this is almost anywhere. I think that's very, very helpful. Blood is fragile, you have to be careful. But having access to it, that's what you're trying to address in hematology disease. That's a tremendously helpful and useful area. So is the trial doable and executable with the resources that you as a small company have is one of the things that we consider when we pick indications. In these cases, the answer is yes.

Makes sense. Jonathan, did you want to add anything?

Sure. So Rocket really developed its pipeline not so much based on a single scientific platform or a core group of diseases, but really based on the premise that even 5, 6 years ago, as we were starting, there was already clinical proof-of-concept that applicable gene therapy technologies could readily address any number of genetic disorders. And that specifically was the lentiviral transduction of hematopoietic stem cells for hematopoietic disorders. And then also had no associated viruses for disorders of heart and muscle and nerve. Within the spectrum of genetic diseases, we really looked at disorders that were clinically serious, where it was possible to get the gene of interest directly into the critical cell of interest and where there were also definable and measurable clinical endpoints so that there is a reasonably straightforward regulatory pathway. And in the process really came to the various disorders that we have in the pipeline. In the initial Rocket programs, these were all disorders where an academic group had made some significant inroads based on their disease and gene therapy expertise but needed a biopharma partner to really take them into clinical development in a way that could generate a replicable bona fide medicine. And our academic partners continue to be a critical part of our development programs. That's University of California, San Diego for Danon disease, Lund University was osteopetrosis. And then 3 of our programs came from this group in Madrid, Spain that goes under the acronym CIEMAT, which is kind of like an NIH in Spain that has a really robust set of programs. Going forward, I think many of our programs are likely to come from our own internal discovery group, which we've been able to build up over the years. And that will be the -- hopefully, the second and third phases of our programs. But the initial ones were all partnered from really tremendous academic partners. And it's been one of the wonderful things about this first 5 years at Rocket. It's been some of the most enjoyable and really robust industry academia collaboration that I've seen in more than 15 years in biopharma.

Great. Thank you. I'll try to keep my questions in conceptual order. We just talked about picking indications and how that's done and what the thought process looks like there. So let's talk about clinical trials next. Talk about what are the pitfalls in develop -- in doing clinical trials for rare hematology and benign hematology. How should Phase I and Phase II trials be designed to get the most bang for your buck? And as I say, what are the key pitfalls that people can get into trouble with, if they don't think carefully about how they design the studies? Jackie, maybe, you want to start? Just take your...

Let me start with the hardest question, right? Start first from the hard one. So I mean, I think the -- we often get the question, I think, about biomarkers versus clinical outcomes. Let me just start with that because I think it's part of the answer to the overall question here. So from our perspective, we think biomarkers can be very helpful in terms of gauging activity of your drugs and things like that. But we -- in the end, clinical outcomes have to carry the day, right? So we think about biomarkers as tools that can help us make decisions about how we take things forward. So in that regard, when you're thinking about trials, including the early ones, you probably want to figure out a way to not only see biomarker activity, but also have some view on what's happening from a clinical standpoint with the drugs. Because we -- I think in the industry, generally speaking, we sometimes can go down the path of saying, well, if I see the biomarker activity early, then later, that's by definition going to translate into a clinical outcome and that might not necessarily be the case. So I think that's one thing. In some of the diseases that we're talking about here, I think we -- maybe right now, don't have quite as much of this to think about, but we certainly will have and it starts already now in terms of what your control arm is and then how you think about the results that you ultimately produce with your therapy versus some of the other therapies that may be already on the market or that are coming. So I think in this benign heme space, the standards of care are evolving pretty rapidly. And so as from now on a go-forward basis, as companies are running clinical trials, you'll have to think a bit about standard of care and how that does or doesn't impact your programs. We're also spending a fair amount of time thinking of and trying to include, in our trial designs, some of the different patient populations. So in some of the diseases that it's very relevant, whether they're transfusion-dependent or nontransfusion-dependent. And then the endpoints that you have around those, of course, could be very different. In our thalassemia program, for example, we're stratifying for alpha thalassemia and beta thalassemia patients. So I think those are some other elements, that depending on the indication, of course, it's important to think about. And because we, of course, want to bring differentiated treatments that really confer a benefit to patients, we're also thinking about both the improving our chances of regulatory success, but also the data package that would come forward in the end in its totality. And then what it means in terms of health care providers' ability to assess whether their patients are really going to benefit from the drug or not. So as an example, sickle cell disease will -- in our pivotal program, we have 2 primary endpoints. And from a statistical standpoint, if we hit on either one of them, we potentially can move forward with a fileable package from a regulatory standpoint. But we want to be able to, with that design, see what we achieve in terms of hemoglobin increase as well as potentially the reduction in vaso-occlusive crisis, for example. And then a variety of other secondary endpoints. I think it's always important to think about your secondary endpoints, including patient-reported outcomes, in any of these trials and how you set that up to really be able to demonstrate clinical benefit as well as quality of life benefits for your patients. So with that, I'll tee it up for somebody else.

Got it.

Thank you, Jackie. I very much agree with Jackie's view and approach in biomarkers versus clinical outcomes. In the 2 indications we are pursuing, ITP and hemolytic anemia, the approval endpoints is platelet counts, which, as I mentioned, is relatively easily measurable. It's a disease in ITP, a disease of bleeding really. But it's -- the biomarkers have been accepted as a way of getting an approval in ITP by simply you have higher platelet counts in this disease characterized by low platelet counts. It's accepted that the clinical outcomes of reduced bleeding is there, though that's not necessarily the approval -- the primary approval endpoint. You definitely measure and monitor, and you do need to demonstrate that. It would be bizarre if you increase platelet counts in the patient populations such as this and did not have an improvement in bleeding episodes, for example, or use of ICUs or hospital stays relative to [indiscernible]. So the good thing about these rare diseases is that the FDA seemingly has accepted these well-measured blood markers as an approvable endpoint to the benefit because it would have been very challenging to do these rare heme diseases had we not had that and had to measure something like mortality or bleeding episodes and how you get to that. So I think that's one of the benefits of rare heme disease. The counterpoint to the rare is that rare is rare, and it's hard to find patients in some of these diseases. As an example, for our warm autoimmune hemolytic anemia trial, about 90 patients. We had to go to about 90 sites across the world, a large, large number of sites in order to recruit this [indiscernible]. So it is challenging. The rare nature of these make it challenging to recruit these patients. They are there, and -- but you have to go and find them. And obviously, they're patients who have medical need. In some cases, medical need but no available therapy means that they're not in the clinic on a regular basis. That makes it also a challenging thing to get done. I think our approach has been to go to many sites so that we can mitigate some of the time frames of enrollment. We've been successful. One of the challenges in the last 1.5 years, as you know, is COVID. And enrolling trials during COVID conditions is incredibly challenging. Given that particularly, unless it's COVID-related, many institutions are not focusing on the enrollment of these trials. And these trials, ours, for example, require a patient to visit a site every 2 weeks. And we worked very hard on getting them enrolled and keeping the sites engaged and active in looking for patients. And fortunately, in the case of warm autoimmune hemolytic anemia, we're nearing completion. And we're delighted by that. Some other products in the area have halted enrollment, and we were able to proceed, nonetheless, by opening up more sites and different places to get it done. So it's challenging. Rare disease is always challenging. But heme has some advantages, I think, and the acceptance of biomarkers for approval, I think, is one of them.

Do you want to add anything, Jonathan?

Sure. I think Jackie and Raul have touched on a lot of the critical elements. One thing I would emphasize is the eligibility criteria is so critical in these rare diseases. Because on the one hand -- well, it's a rare disease. You don't want to be turning people away. But on the other hand, from an efficacy perspective, you -- if you want to show a benefit, you really need a pretty precisely-defined subset of a given disorder because otherwise, you are really mixing different patient populations and potentially jeopardizing your ability to demonstrate a meaningful efficacy benefit. And then ditto, there are going to be situations where patients' illness is too far progressed, especially in some of these more severe childhood illnesses. If patients have had devastating sequelae of their disease already, and they may be in a situation where they're past the point where a given therapeutic, even addressing the disease at its genetic core, may no longer be really, really beneficial. So as much as the temptation is to be inclusive, one, at times, needs to be exclusive from a safety perspective or an efficacy perspective. And then I think the other critical challenge that Jackie touched on is the natural history element because although sometimes you -- one is operating in a disease area where there may be dozens or hundreds of publications, sometimes very few of them are actually honing in on the specific endpoints that a sponsor needs to demonstrate efficacy. And one, in that case, has to, in one way, shape or form, go back to the drawing board and figure out how those endpoints have played out in patients either in a prospective or retrospective way. And that could sometimes take a lot of time and energy to adequately tease out in a way that can serve as an appropriate external control.

Okay. You all touched on some important themes related to biomarkers and clinical outcome measures. What are the interplay of those 2? And if you have a good clinical outcome measure, do you still need a biomarker? Does it matter? Just curious, your thoughts on that.

I think it depends what the FDA tells you, to be honest with you. And if they say the biomarker's acceptable, that's good. If clinical outcome is required, and that's what's required. So in some ways, it will be dictated to you it to a degree.

Okay.

We've been operating under the assumption that health authorities, either the FDA or the EMA or both are going to want to see more and more. They're going to want to see that we've corrected things at the genetic level. They're going to want to see clinically measurable laboratory or other clinical parameters, and they're going to want to see some other scientific proof-of-concept that we're actually making a difference at a molecular or some other biochemical level. And that our data package is going to need to have the belt and the suspenders.

That's right. And we haven't talked about payers. If we talk about payers and you get into that whole discussion with access as well. I mean, clearly, if you -- clinical outcomes are going to carry the day, except for in those situations that Raul has spoken about where the biomarkers are agreed already to be good [indiscernible] for that. But I think having both also helps with how you position the treatments with health care providers and can help mechanistically explain how the drugs are working from a biomarker standpoint and then you get the clinical outcomes that go together. So hopefully, in an ideal situation, you get both and they tell a consistent story.

Makes sense. Well, we've talked about picking indications, talked about -- a little bit about clinical trial design. The next step, obviously, is commercial and launch. So each of you are at different points in that trajectory. Raul, you've already launched a product, obviously. Jackie, you are on the doorstep of launching. And Jonathan, I think you have a little bit further to go. But the question is, what do you need to do to get it right when you launch in benign heme? What are the key things that matter that can ensure a successful launch? And what are some of the pitfalls that you want to avoid? Maybe, Raul, you want to start since you've already done this?

Well, I think it's a challenging launching a drug period, especially a first drug in the company. That's for sure. You're building an organization and you're having it launched. And I think one of the things that -- in fact, someone asked me for a piece of advice. Hire very experienced people in doing what they're doing and give them adequate time to do it. And that implies adequate resources to do it. When we were launching our first product, we got very good advice in saying, make sure you have all the organization, say, for the sales force perhaps in place maybe over a year prior to your anticipated launch. And that's expensive, requires a lot of planning, a lot of work, but we were able to do that. And I think that sets us up very well for a successful launch. And so that anticipatory investment, I think, is absolutely critical in hiring people that have deep experience in it. One of the things about being in Boston, New York or the Bay Area, is that if your company internally doesn't have that capability and if it's your first launch, you don't, the good thing about being in these geographies is that within a few miles of this are many people who have very deep experience doing that. That's why we're in this area because we can tap into an employee base that has that experience, hire really talented people who have very deep experience. With our sales force, for example, we have people that have 10, 15 years of experience selling heme-onc products successfully with numerous track records of success. You have to do that, number one. I think the other key challenge is you have to identify the right doctors. And that's not easy, actually, and that comes with having some resources devoted to that in advance. But when you launch, you find that, no, that actually isn't the doctor who treats this indication, someone else does, maybe someone else in the same practice. And you have to refine who the treating doctors are that you want to address with your organization. And it's not always readily available. That's something that takes a fair amount of investment in refinement and you get better at it over time. And one of the challenges, I think, in rare heme indications is that these doctors also in heme-onc, for example, they treat numerous other diseases, a large number of other products. There's a large call on their times from various companies, and you have to have a sales organization that is sufficiently experienced that has those resources so that they can access those doctors when other companies are also looking to do the same. But there was real challenges in terms of getting their share of mind. Especially in times such as COVID, where even less time is available, simply because they have less time for Zoom calls as a requirement. But I think that's been a key area of focus and success for us. We've hired very experienced people who, as a result, had strong relationships with treating heme-oncs that treated the disease well. I think more further challenge, I think, maybe for us and maybe for others as well, it's been -- there's hematologists who are, in many cases, the thought leaders in the area; and heme-oncs who in fact, are much more numerous and treat a larger number of patients. For us, ASH is important for hemes and ASCO is important for heme-oncs. So you have to address both constituencies within this area. And that presents a challenge to some companies. It's something that maybe pays -- it's probably useful to get some thoughts in terms of who your audiences are because there might be a bit [indiscernible] than you think it is.

Interesting, interesting. Jackie?

Yes. So maybe real quick. I mean, we do have the benefit of the past experience in malignant hematology at Agios, something that helps us some. But coming to market with the first approved product for pyruvate kinase deficiency is going to be both an opportunity and a challenge in some respects, one that we're very excited about. And really, when we think about PKD, specifically, I would highlight probably 4 things that were the most focused on. The first one is driving diagnosis of PKD, the disease itself, as well as identifying patients. And we've talked many times about our patient identification efforts over the years and the things that we've been doing there. And that -- and sometimes, investors get almost a little bit overly focused on that because it is important because out of the gate, you want to know that you've got a certain number of patients that you can go after. But it's as important for the long-term to improve diagnosis of PKD and in other diseases like that. So we're very focused on that, the Anemia ID program that we've rolled out, where we provide testing kits free of charge to physicians, and they can test for more than just PKD. And we think that's a nice service for them. So driving diagnosis and identifying patients is one. In educating, and it's probably the case for some other diseases as well, around the need to treat these diseases and the urgency to treat these diseases, some of what we're doing there. Now we have the benefit of our -- the totality of our pivotal clinical program data and the presentations that we made at EHA. We can get out and educate based on that data, which included positive patient-reported outcomes, but also all the clinical outcomes. And then we've also over time produced more and more information about the burden of disease for PKD. And I think that's whether it's PKD or some other diseases, I think that it's important over time to generate that data around the aspects of the burden of disease so that the need becomes more clear, both for physicians as well as payers that we need to treat these patients. The third thing is to ensure access. And again, for some of these diseases that, unlike cancer, are not obviously fatal in a short period of time, you want to work very hard on access because it doesn't do any good to have that a drug approved if we can't get it to patients. So access is number 3. And then eventually when you get patients on drug, and we've seen that in some other therapeutic areas, you want to make sure that you address adherence and compliance with patients staying on drug. So if they feel better, that clearly helps. But you also want patients to understand the long-term impacts of their disease and how, if they stay on a therapy, they may be able to avoid some of those negative long-term impacts of their disease.

Okay, great. Jonathan, did you want to add anything on the launch question?

I think that Jackie and Raul have covered this beautifully. I think just to summarize, I would emphasize that it's really about knowing the patient and family voice, knowing the caregiver community. For us, because we have multiple programs, some of our programs are "benign heme" and many of our programs are in disorders that are anything but benign that are often fatal or life-threatening in the early years of life. So it's definitely not one size fits all. Most of it is about listening to all these different voices and then really thinking about all the obstacles and coming up with a pretty tailor-made approach. What works for a red cell hemolytic anemia might not work for a neutrophil immunodeficiency, might not work for a bone marrow failure syndrome. And in each case, it's about spending a lot of time listening to the experts and listening to the patients and families and their stories, and then making sure that the program is designed in a way that's cognizant of those concerns.

Makes a lot of sense. All right. So we've got about 5 or 6 minutes left. So we could just do a quick lightning round here, so to speak, just more company-specific questions. For you, Jackie, at Agios, I believe you are starting 2 pivotal trials, one in thalassemia, another one in sickle cell by the end of the year. If you could briefly outline what were the key learnings from your Phase I and Phase II studies that informed the design of these Phase IIIs and what's left to do before you can actually kick these trials off?

Yes. So let me answer the last part of your question first. We're operationalizing both of our pivotal programs in thalassemia and sickle cell disease now. So we're really down in the degree of the reads of just getting the sites up and running and we're on track to have our first patients initiated in each of those trials before the end of the year, in line with our stated objectives. So I think some of what we talked about earlier has informed the design of those trials. Clearly, we listened to regulators and take that regulatory feedback into consideration. But what we want to do at the end of the day is generate data packages that not only will give us the best chance of regulatory approval, but they also -- they tell the story of what the drug is really doing for patients. And so in both of these pivotal programs, we've thought about that. On the thalassemia program for example, we are running simultaneously both nontransfusion-dependent and transfusion-dependent trials. Within each one of those, we will stratify for alpha thalassemia and beta thalassemia patients. And then we have a variety of other secondary endpoints that are focused on hemolysis, but as well how patients feel and how they function. And we did that in the PKD program, and we learned something from that -- the success of that PKD program and have taken that into thalassemia and similarly, in sickle cell disease. So I think we also, with this drug, have learned a lot about the safety profile of it. We've now been in the clinic with mitapivat for our lead asset for 5 or 6 years. And so even though each one of these indications is a little bit different [indiscernible] or a lot different in terms of patient experience, but we've learned a lot about the safety profile of the drug in hemolytic anemias in general. And I think that has helped us think about the design of these trials as well, and we've been able to build on that. So those are probably some of the key considerations, and I'll let my fellow panelists talk.

Okay. Raul, curious for you. Moving TAVALISSE into earlier lines of therapy. Talk about the strategy there and how you're leveraging some of this post hoc data that you've generated in the earlier line settings.

So in ITP, what we've seen is that TAVALISSE works even better in earlier lines of therapy. And there's many more patients in those earlier lines of therapy. So that's a key focus of us is to move into those earlier lines of therapy and have doctors trials there because the success is even better there. And so what we've done, though, with this COVID, unfortunately, what has happened is the awareness of that is not as high as we would have liked. We simply haven't been out there enough in order to make sufficient progress with that data. The data is really excellent in terms of that durability data as well as the early line data with our product. So what we've done, 2 things. More and more of our interactions are in personnel. Last quarter, about half of them were in person rather than solely in video, which is the case prior. So that trajectory hopefully continues. And to help that out, we increased the size of our sales force from 39 to 55 reps, which is really good because now we have a broader organization to tell that story. It's a very compelling story. What we see, though, is when the physicians are aware of that story, our earlier line data, durability, that -- it impacts their prescribing patterns. That's exactly what we see. So there's tremendous opportunity there. And so really, our focus is continuing to move up into earlier lines. And by doing so, with more and more in-person interactions and with a larger organization is a way of doing it. And I'm looking forward to -- I can't tell you how much I'm looking forward to spending the next [indiscernible] so we can make real progress in that.

You and me alike. And Jonathan, I believe that you will have data in the fourth quarter of this year for the Fanconi anemia program as well as the leukocyte adhesion deficiency program. Could you just give us a quick sense as to what types of data we should expect from those 2 readouts later this year?

Right. And those are both of our registrational trials. And it really will be longer follow-up on existing patients and additional results from a greater number of patients relative to what we're able to present at ASGCT in May of this year. So more patients and longer follow-up. And very hopefully, similar results in terms of efficacy and safety to what we showed from the initial group in recent months.

And then how long would it take do you think before you could file the BLA?

Well, we haven't provided guidance with respect to the timing of BLA filing, but this is something that we hope to be able to provide guidance on soon and we really hope to be in a position to file BLAs over the course of the coming year or 2, and we'll be able to be more granular about that as we get later into the year and into 2022.

Okay. Got you. Well, thank you all so very, very much. Really appreciate your comments and your insights. Best of luck with your drug pipelines, and we look forward to hosting you again on a future occasion. Thank you.

Thank you.

Yigal, nice talking to you.

Thank you, Yigal.

You're welcome.